A Complementary Chemical and Genomic Screening Approach for Druggable Targets in the Nrf2 Pathway and Small Molecule Inhibitors to Overcome Cancer Cell Drug Resistance.
A Complementary Chemical and Genomic Screening Approach for Druggable Targets in the Nrf2 Pathway and Small Molecule Inhibitors to Overcome Cancer Cell Drug Resistance.
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DOI：
10.1021/acschembio.7b01025
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发表时间：
2018-05-18
影响因子：
4
通讯作者：
Luesch H
中科院分区：
文献类型：
--
作者：
Matthews JH;Liang X;Paul VJ;Luesch H
对化疗的抗药性是治疗各种不同类型癌症的主要障碍。化疗耐药是由癌细胞通过多种不同的机制实现的，这些机制既可以是化合物特异性的，也可以是一般性的。一种新出现的非特异性化疗耐药机制依赖于转录因子Nrf2的过度激活。正常情况下，Nrf2水平受到泛素-蛋白酶体系统的严格调控，然而，负责这一调节的基因突变在许多癌症类型中都是常见的，导致Nrf2表达增加，其下游靶基因激活，并对多种化疗药物产生耐药性。出于这个原因，人们对发现能够减弱这种耐药机制的Nrf2小分子抑制剂产生了相当大的兴趣。为此，我们筛选了两个商业上可用的已知生物活性小分子文库，以确定潜在的Nrf2抑制剂。为了增加这个屏幕的广度，我们还筛选了一个以大多数可药物基因组为靶点的RNAi文库，以识别目前没有被小分子靶向的Nrf2抑制因子靶点。为了补充商业化学和基因组文库的筛选，我们筛选了一小部分从海洋蓝藻中分离出来的专有天然产物，其中包括肌动蛋白靶向和未表征但具有生物活性的化合物。通过这些努力，我们已经确定了三类化合物：心脏糖苷类化合物、STAT3抑制剂和肌动蛋白干扰剂作为Nrf2抑制剂，它们能够减弱Nrf2的活性，并与化疗药物在非小细胞肺癌A549细胞中具有协同作用。此外，我们还发现，蚂蚁内酯A通过一种迄今尚未被描述的机制来发挥Nrf2的调节活性。此外，我们还鉴定了一组可能的Nrf2靶点，包括转录因子Twist1和ELF4、蛋白激酶NEK8、TAK1激酶调节因子TAB1和双特异性磷酸酶DUSP4。这项研究拓宽了抑制Nrf2活性的机制范围，这将有助于新型Nrf2抑制剂的表征，并允许设计靶向特异性筛选程序来识别更多。
Resistance to chemotherapy is a major obstacle in the treatment of a wide array of different types of cancer. Chemotherapeutic drug resistance is achieved by cancer cells by a variety of different mechanisms, which can be either compound specific or general. An emerging mechanism for non-specific chemotherapeutic drug resistance relies on hyperactivity of the transcription factor Nrf2. Normally Nrf2 levels are tightly regulated by the ubiquitin-proteasome system, however mutations in genes responsible for this regulation are common in many cancer types, resulting in increased expression of Nrf2, activation of its downstream target genes and resistance to a variety of chemotherapeutic agents. For this reason, there has been considerable interest in the discovery of small molecule inhibitors of Nrf2 capable of attenuating this resistance mechanism. To this end, we have screened two commercially available libraries of known biologically active small molecules to identify potential Nrf2 inhibitors. To increase the breadth of this screen we have also screened an RNAi library that targets the majority of the druggable genome to also identify Nrf2-inhibitor targets that are not currently targeted by small molecules. To complement the commercial chemical and genomic library screening, we screened a small collection of proprietary natural products isolated from marine cyanobacteria, which included actin targeting and uncharacterized but biologically active compounds. Through these efforts, we have identified three classes of compounds: cardiac glycosides; Stat3 inhibitors; and actin disrupting agents as Nrf2 inhibitors that are able to attenuate Nrf2 activity and synergize with chemotherapeutic agents in the non-small cell lung cancer cell line A549. In addition, we found that grassypeptolide A exerts Nrf2 modulatory activity via a thus far uncharacterized mechanism. In addition, we have identified a set of putative Nrf2-targets comprising the transcription factors TWIST1 and ELF4, the protein kinase NEK8, the TAK1 kinase regulator TAB1 and the dual specific phosphatase DUSP4. This study broadens the range of mechanisms through which inhibition of Nrf2 activity can be achieved, which will facilitate the characterization of novel Nrf2 inhibitors, and allow the design of target specific screening procedures with which to identify more.
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影响因子：
11.5
作者：
Homma, Shinsuke;Ishii, Yukio;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki
影响因子：
16
作者：
Padmanabhan, B;Tong, KI;Yamamoto, M
通讯作者：
Yamamoto, M
影响因子：
4.6
作者：
Harder B;Tian W;La Clair JJ;Tan AC;Ooi A;Chapman E;Zhang DD
通讯作者：
Zhang DD
影响因子：
10.5
作者：
Jaramillo MC;Zhang DD
通讯作者：
Zhang DD
DOI：
10.1073/pnas.1711088114
发表时间：
2017-10-24
影响因子：
11.1
作者：
Herbert AL;Fu MM;Drerup CM;Gray RS;Harty BL;Ackerman SD;O'Reilly-Pol T;Johnson SL;Nechiporuk AV;Barres BA;Monk KR
通讯作者：
Monk KR